Increasing biocompatibility of stents through CD47 functionalization

通过 CD47 功能化提高支架的生物相容性

• 批准号: 8651913
• 负责人: Stanley Joseph Stachelek
• 金额: $ 24.37万
• 依托单位: CHILDREN'S HOSP OF PHILADELPHIA
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-04-15 至 2015-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8651913
• 关键词: Address; Adhesions; Affinity; Angioplasty; Anti-Inflammatory Agents; Anti-inflammatory; Apoptosis; Area; Arteries; Attenuated; Binding; Biocompatible Materials; Biological; Biological Assay; Blood; Blood Platelets; Blood Vessels; CD47 gene; Cardiology; Cardiovascular system; Carotid Arteries; Cell Communication; Cell Surface Proteins; Cell-Matrix Junction; Cells; Chemicals; Chemistry; Clinical; Complement; Coronary; Deposition; Doctor of Medicine; Doctor of Philosophy; Drug Formulations; Electron Microscopy; Erythrocytes; Evans blue stain; Event; Functional disorder; Harvest; Human; Immobilization; Immune; Immunofluorescence Immunologic; Immunohistochemistry; Immunology; Implant; In Vitro; Inflammatory; Inflammatory Response; Integral Membrane Protein; Investigation; Lead; Ligands; Link; Lysine; Medical Device; Medicine; Metals; Methodology; Modeling; Modification; Outcome; PTPNS1 gene; Patients; Peripheral; Platelet Activation; Polymers; Polyurethanes; Polyvinyl Chloride; Property; Proteins; Protocols documentation; Publishing; Rattus; Recombinants; Research Personnel; Role; Science; Signal Transduction; Simulate; Solutions; Stainless Steel; Steel; Stents; Sterilization; Structure; Surface; Synthesis Chemistry; T-Lymphocyte; Techniques; Technology; Testing; Therapeutic; Therapeutic Studies; Time; Tissues; base; biomaterial compatibility; bisphosphonate; cell type; clinical application; ilium; implantation; improved; in vivo; innovation; interest; monocyte; nanoparticle; nanoscale; neutrophil; novel; novel strategies; polyallylamine; prevent; public health relevance; receptor; research study; response; restenosis; vascular inflammation

DESCRIPTION (provided by applicant): The pathophysiology associated with endovascular stent usage is well documented and is observed in up to 50% of all patients receiving the medical device. Unfortunately there has been a paucity of innovative solutions to prevent the untoward effects, such as in-stent restenosis and neointimal formation, of cardiovascular stent deployment. Biofunctionalizing the blood-contacting surface of medical devices, with bioactive therapeutic molecules, would hypothetically attenuate the aberrant hemocompatibility issues that are observed in stent usage. CD47 has been identified as a ligand for the immune inhibitory receptor SIRP¿ and has been shown to confer "self" status on xenotransplanted red blood cells and synthetic nanoparticles. Dr. Stanley J. Stachelek, one of this project's co-Principle Investigator (PI) and an expert on developing strategies to address the inflammatory response to cardiovascular biomaterials, has recently described a platform technology to reduce the inflammatory response to a range of biomaterials such as polyvinyl chloride (PVC) and polyurethane (PU), by covalently linking a ubiquitously expressed cell surface protein, CD47, to the polymers' surface. Complementing Dr. Stachelek's expertise, Dr. Ilia Fishbein, M.D., Ph.D., the other co-PI on the project, has published extensively on developing new and innovative strategies to enhance endovascular stent biocompatibility. Drawing from the expertise of these two investigators, this proposal will test the hypothesis that recombinant CD47 can be immobilized onto the surface of endovascular stents to decrease the pro-thrombotic and pro-inflammatory events that are observed after stent deployment. The proposal will have two Specific Aims. In the first aim, the investigators will optimize the attachment of recombinant CD47 to stainless steel surfaces. Additional studies will be performed to characterize, using in vitro and ex vivo methodologies, the anti-inflammatory properties of CD47 functionalized metal surfaces. Lead formulations of CD47 modified metal surfaces will then be used in the second and final Specific Aim where a rat model of stenting angioplasty will be used to assess the efficacy of CD47 modified stents in enhancing hemocompatibility and reducing neointimal formation and in-stent restenosis. This proposal, which blends expertise and concepts from cardiology, synthetic chemistry, immunology, and materials science will contribute to developing a novel and innovative therapeutic strategy to address the aberrant effects of cardiovascular stent usage.

描述(由申请人提供)：与血管内支架使用相关的病理生理学有很好的记录，并在接受该医疗设备的所有患者中观察到高达50%。不幸的是，对于心血管支架置入所产生的不良反应，如支架内再狭窄和新生内膜形成，目前尚缺乏创新的解决方案。用生物活性治疗分子对医疗器械与血液接触的表面进行生物功能化，假设可以减轻支架使用中观察到的异常血液相容性问题。CD47已被确认为免疫抑制受体SIRP的配基，并已被证明赋予异种移植的红细胞和合成纳米颗粒“自我”状态。斯坦利·J·斯塔切莱克博士是该项目的联合原则调查员(PI)之一，也是开发应对心血管生物材料炎症反应的策略方面的专家，他最近描述了一项平台技术，通过将普遍表达的细胞表面蛋白CD47共价连接到聚合物表面，来降低对聚氯乙烯(PVC)和聚氨酯(PU)等一系列生物材料的炎症反应。作为对Stachelek博士专业知识的补充，该项目的另一位合作者Ilia Fishbein博士，医学博士，博士发表了大量关于开发新的创新策略以增强血管内支架生物兼容性的文章。借助这两位研究人员的专业知识，这项提议将检验这样一个假设，即重组CD47可以固定在血管内支架的表面，以减少支架置入后观察到的血栓形成和促炎事件。该提案将有两个具体目标。在第一个目标中，研究人员将优化重组CD47在不锈钢表面的附着。将进行更多的研究，使用体外和体外方法，表征CD47功能化金属表面的抗炎特性。然后，CD47修饰的金属表面的铅配方将用于第二个也是最后一个特定目标，其中将使用支架血管成形术的大鼠模型来评估CD47修饰支架在增强血液相容性、减少新的内膜形成和支架内再狭窄方面的效果。这项建议融合了心脏病学、合成化学、免疫学和材料科学的专业知识和概念，将有助于开发一种新颖和创新的治疗策略，以解决心血管支架使用的异常影响。